Biology subjects

Schneider, D. L.

Publications and source records attributed to Schneider, D. L..

8 recordsLinked to original sources

bioRxiv2026

Tryptophan Restores Recovery Competence Following Starvation in the Absence of Lysosomal Amino Acid Sensing

How organisms recover from starvation to nutrient-replete physiology remains poorly understood. In C. elegans, we previously observed that transcription factor hlh-30 or a combination of glucose and linoleic acid in its absence are essential for survival with refeeding following starvation, i.e. recovery competence. A forward genetic screen to evaluate mechanisms identified depd-5, which encodes a GATOR1 subunit, loss of which is expected to impair amino acid sensing with unrestrained raga-1 and mTOR activation. Surprisingly, glucose refeeding reduced recovery competence in depd-5(lf, loss-of-function) animals, which was rescued by amino acids, specifically tryptophan. Increasing tryptophan levels in depd-5(lf) worms through supplementation, reduced tryptophan catabolism with tdo-2 ablation and prolonged starvation restored recovery competence. raga-1(gf, gain-of-function) recapitulated whereas raga-1(lf) rescued the impaired recovery competence in starved depd-5(lf) worms. An analogous DEPDC5 mutation in mammalian cells impaired starvation-induced mTOR inactivation. We conclude that tryptophan counters unrestrained mTOR activity to restore recovery competence following starvation.

cell biology↗

bioRxiv2026

Lysosomal Expansion Compartments Mediate Zinc and Copper Homeostasis in Caenorhabditis elegans

Zinc is an essential transition metal that participates in many biological processes. In C. elegans, excess zinc is stored in lysosomes in intestinal cells; this process involves increasing the expression of the zinc transporter CDF-2 and remodeling of lysosomes characterized by an increase in the volume of the expansion compartment. To determine if this is a more general property, we investigated other metals. Here we report that lysosomes are remodeled in response to excess copper, manganese, and cadmium, with each metal causing an increase in the volume of the expansion compartment. Mutants with a reduced number of lysosomes were hypersensitive to growth retardation caused by excess copper and manganese, suggesting metal toxicity is prevented by metal sequestration in lysosomes. Using a novel method to analyze isolated lysosomes by X-ray Fluorescence Microscopy we demonstrated that zinc, copper and manganese are detectable in the lumen of lysosomes. To further analyze copper, we examined localization of CUA-1.1, a copper transporter that moves copper into the lumen of lysosomes. Like the zinc transporter CDF-2, CUA-1.1 localizes to both the acidified and expansion compartments in excess copper. These results indicate that the same intestinal lysosomes store zinc, copper and manganese. Lysosome remodeling characterized by an increase in volume of the expansion compartment is not specific to zinc but is a more general phenomenon during metal storage in lysosomes.

molecular biology↗

bioRxiv2026

Zinc excess promotes lysosome remodeling by activating HLH-30/TFEB through the action of the high zinc sensor HIZR-1.

Zinc is an essential element that plays many roles in animals. Since excess zinc is toxic, animals have evolved sophisticated mechanisms to achieve homeostasis. A conserved mechanism is to store excess zinc in specialized lysosomes, which contributes to zinc detoxification and provides a supply when zinc becomes limiting. In C. elegans excess zinc conditions promote an increase in lysosome-related organelles called bilobed granules. Defining how zinc-regulated transcription drives the observed lysosome remodeling is key to understanding zinc homeostasis processes. Here we describe a positively regulated zinc cascade controlled by hizr-1 and hlh-30/TFEB, which encode the C. elegans high zinc sensor and the master regulator of the autophagy-lysosomal pathway, respectively; essential for connecting excess zinc homeostasis to lysosome biogenesis and remodeling. Our transcriptomic, genetic, and bioinformatic studies indicate that hizr-1 and hlh-30 are necessary and sufficient to activate transcription of lysosome genes under excess zinc conditions. In our regulatory model, zinc binding activates HIZR-1 protein, which accumulates in the nucleus and activates genes containing the HZA enhancer, including hlh-30. HLH-30 protein accumulates in the nucleus and activates genes containing the E-box enhancer. Genetic analysis of loss-of-function mutants demonstrated that both hizr-1 and hlh-30 are necessary for animals to tolerate excess zinc. Furthermore, HLH-30 promotes the increase in the number of acidified compartments, whereas HIZR-1 promotes the increase in the volume of the expansion compartment. These results define a genetic pathway that responds to excess zinc by increasing the number of lysosome-related organelles and their capacity to store and detoxify cytosolic zinc.

genetics↗

bioRxiv2025

Environmental NaCl affects C. elegans development and aging

Sodium is an essential nutrient, but is toxic in excess. In humans, excessive dietary sodium can cause high blood pressure, which contributes to age-related diseases including stroke and heart disease. We used C. elegans to elucidate how sodium levels influence animal aging. Most experiments on this animal are conducted in standard culture conditions: Nematode Growth Medium (NGM) agar with a lawn of E. coli. Here, we report that the supplemental NaCl in standard NGM, 50 mM, accelerates aging and decreases lifespan. For comparison, we prepared NGM with reduced NaCl or excess NaCl. Considering reduced NaCl as a baseline, wild-type worms on standard NGM displayed normal development and fertility but reduced lifespan and health span, indicating toxicity in old animals. The long-lived mutants daf-2, age-1, and nuo-6, cultured on standard NGM, also displayed reduced lifespan. Thus, NaCl in standard NGM accelerates aging in multiple genetic backgrounds. Wild-type worms on excess NaCl displayed delayed development and reduced fertility, and reduced lifespan and health span, indicating toxicity in both young and old animals. These results suggest that young animals are relatively resistant to NaCl toxicity, but that aging causes progressive sensitivity, such that old animals display toxicity to both standard and excess NaCl. We investigated pathways that respond to NaCl. Young animals cultured with excess NaCl activated gpdh-1, a specific response to NaCl stress. Old animals cultured with excess NaCl activated gpdh-1 and hsp-6, a reporter for the mitochondrial unfolded protein response. Thus, excess NaCl activates multiple stress response pathways in older animals.

developmental biology↗

bioRxiv2024

A single high-zinc activation enhancer can control two genes oriented head-to-head in C. elegans

Enhancers play critical roles in gene expression, but a full understanding of their complex functions has yet to be defined. The cellular response to excess zinc levels in C. elegans requires the HIZR-1 transcription factor, which binds the high-zinc activation (HZA) enhancer in the promoters of multiple target genes. Cadmium hijacks the excess zinc response by binding and activating HIZR-1. By analyzing the genome-wide transcriptional response to excess zinc and cadmium, we identified two positions in the genome where head-to-head oriented genes are both induced by metals. In both examples, a single predicted HZA enhancer is positioned between the two translational start sites. We hypothesized that a single enhancer can control both head-to-head genes, an arrangement that has not been extensively characterized. To test this hypothesis, we used CRISPR genome editing to precisely delete the HZAmT enhancer positioned between mtl-2 and T08G5.1; in this mutant, both head-to-head genes display severely reduced zinc-activated transcription, whereas zinc-activated transcription of more distant genes was not strongly affected. Deleting the HZAcF enhancer positioned between cdr-1 and F35E8.10 caused both head-to-head genes to display reduced cadmium-activated transcription, whereas cadmium-activated transcription of more distant genes was not strongly affected. These studies rigorously document that a single HZA enhancer can control two head-to-head genes, advancing our understanding of the diverse functions of enhancers. Article SummaryEnhancers are critical for gene expression, but a full understanding their functions has yet to be elucidated. We discovered two positions in the C. elegans genome where a pair of head-to-head oriented genes are both transcriptionally activated by excess zinc and/or cadmium; in both cases, one high-zinc activation (HZA) enhancer is positioned between the translation start sites. When these HZA enhancers were deleted by genome engineering, both head-to-head genes lost metal-activated transcription. These results demonstrate that a single HZA enhancer can control two head-to-head genes, advancing the understanding of enhancer function.

genetics↗

bioRxiv2023

The ACE-inhibitor drug captopril inhibits ACN-1 to control dauer formation and aging

The renin-angiotensin-aldosterone system (RAAS) plays a well-characterized role regulating blood pressure in mammals. Pharmacological and genetic manipulation of the RAAS has been shown to extend lifespan in C. elegans, Drosophila, and rodents, but its mechanism is not well defined. Here we investigate the angiotensin-converting enzyme (ACE) inhibitor drug captopril, which extends lifespan in worms and mice. To investigate the mechanism, we performed a forward genetic screen for captopril hypersensitive mutants. We identified a missense mutation that causes a partial loss-of-function of the daf-2 receptor tyrosine kinase gene, a powerful regulator of aging. The homologous mutation in the human insulin receptor causes Donohue syndrome, establishing these mutant worms as an invertebrate model of this disease. Captopril functions in C. elegans by inhibiting ACN-1, the worm homolog of ACE. Reducing the activity of acn-1 via captopril or RNAi promoted dauer larvae formation, suggesting acn-1 is a daf gene. Captopril-mediated lifespan extension xwas abrogated by daf-16(lf) and daf-12(lf) mutations. Our results indicate that captopril and acn-1 control aging by modulating dauer formation pathways. We speculate that this represents a conserved mechanism of lifespan control. Summary StatementCaptopril and acn-1 control aging. By demonstrating they regulate dauer formation and interact with daf genes, including a new DAF-2(A261V) mutant corresponding to a human disease variant, we clarified the mechanism.

developmental biology↗

bioRxiv2022

Notch signaling in germ line stem cells controls reproductive aging in C. elegans

Reproductive aging in females often occurs early in life, resulting in a substantial post-reproductive lifespan. Despite the medical importance of age-related infertility, relatively little is known about mechanisms that control this age-related decline. C. elegans is a leading system for aging biology due to its short lifespan and powerful experimental tools, and detailed descriptions of molecular and cellular changes in the gonad during reproductive aging were recently reported. Here we show that reproductive aging occurs early in life in multiple species in the genus Caenorhabditis, indicating this is a feature of both female/male and hermaphrodite/male species. In mutants previously established to display delayed reproductive aging (daf-2, eat-2, phm-2), we observed correlations between changes in the distal germline and changes in egg-laying, consistent with the model that distal germline changes are a cause of reproductive aging. By screening for additional mutants that delay reproductive aging, we identified an allele of che-3 with impaired sensory perception that displayed increased progeny production in mid-life, a pattern of reproductive aging distinct from previous mutants. To directly test the role of Notch signaling in the distal germline, we analyzed the effect of ectopic expression of the Notch effector gene SYGL-1. Ectopic expression of SYGL-1 was sufficient to delay reproductive aging, suggesting that an age-related decline in Notch signaling in the distal germline is a root cause of reproductive aging.

genetics↗

bioRxiv2021

Lysosome-related organelles contain an expansion compartment that mediates delivery of zinc transporters to promote homeostasis

Lysosome-related organelles play evolutionarily conserved roles in zinc storage, but mechanisms that control zinc flow in and out are not well understood. In C. elegans intestinal cells, the CDF-2 transporter stores zinc in these organelles during excess. Here we identify ZIPT-2.3 as the transporter that releases zinc during deficiency. The expression levels of CDF-2 and ZIPT-2.3 are reciprocally regulated in zinc excess and deficiency, establishing a fundamental mechanism of homeostasis. Super-resolution microscopy demonstrated these organelles are composed of a spherical acidified compartment and a hemispherical expansion compartment. The expansion compartment inflates during zinc excess and deficiency by vesicle fusion delivering zinc transporters. These results identify an unexpected structural feature of lysosome-related organelles that facilitates rapid transitions in the composition of zinc transporters to mediate homeostasis.

cell biology↗